The purpose of this application is to support the patient-oriented research program and career development of Patrick J. Brown, PhD, a fellowship-trained academic researcher and clinical psychologist at Columbia University. Dr. Brown's overall goal is to develop into an independent investigator with a focus on the assessment and treatment of diagnostically complex geriatric patients with neuropsychiatric disorders. The depressed, frail phenotype represents the most promising avenue to understand how to improve intervention outcomes for geriatric patients with diagnostically complex medical and psychiatric comorbidity. The complexity of this clinical population requires Dr. Brown receive cross training in the principles of geriatric medicine to apply these principles to psychiatric interventions research. As such, he has constructed a multidisciplinary training plan under the mentorship of Dr. Steven Roose, a psychiatrist and authority on the clinical, demographic, and treatment factors affecting response to antidepressants, Dr. Mathew Maurer, a cardiologist with research interests in cardiovascular health and anergia in older patients, and Dr. Linda Fried, a geriatrician, epidemiologist and expert in the concept of frailty, along with advisors in neuropsychology, psychopharmacology, biostatistics, and responsible conduct in research. During the proposed award, Dr. Brown will obtain formal training via coursework, patient-oriented experiences, and expert tutelage in 1) the assessment and understanding of the biological, neuropsychological, and physical characteristics common to frailty and depression, 2) the design, conduct, and analysis of therapeutic interventions, and 3) the complex ethical issues in geriatric research. The overall goal of this research proposal is to understand the depressed frail phenotype. Although depression and frailty individually result in dire outcomes for patients and families and appear to be phenomenologically and physiologically associated, the syndrome of frailty has never been explicitly studied in the context of late life depression. Based on his pilot data and the diagnostic complexities of these two conditions, Dr. Brown had constructed a model of this phenotype and hypothesized that the presence of specific frailty characteristics at baseline will diminish response to antidepressant treatment. To investigate this model, Dr. Brown will conduct a 12-month deconstruction of the depressed, frail phenotype using antidepressant medication. In doing so, Dr. Brown will also assess markers of chronic inflammation and malnutrition in this older depressed frail population to begin to evaluate the potential mechanisms underlying the phenotype, and he will investigate the impact of baseline frailty characteristics on long-term improvement in activity levels and disability. At the end of this proposal, Dr. Brown will be better able to answer how the syndrome of frailty impacts the diagnosis of late life depression, and whether the syndrome of frailty diminishes response to antidepressant treatment. With this experience and skill set, Dr. Brown will combine the knowledge gained from both geriatric medicine and psychiatry to use multidisciplinary assessment techniques to refine our understanding of diagnostically complex geriatric patients with neuropsychiatric disorders and personalize therapeutic interventions targeted to maximize treatment outcome.